Trisomy is the most common genetic abnormality in our species, occurring in at least 3-4% of an clinically recognized pregnancies. As a class, trisomy is responsible for at least 25% of spontaneous abortions and, among liveborn individuals, it is the leading known cause of mental retardation. Despite its high rate of occurrence and obvious clinical importance, we still know surprisingly little about the mechanism of origin of trisomy. In the proposed studies, we intend to combine different molecular approaches to study the underlying causes of human trisomy. In one set of investigations we will focus on the genesis of maternally-derived trisomies, conducting studies to determine the effect of aberrant recombination on non-disjunction and to examine the basis of the maternal age effect on trisomy. In a second set of studies, we will examine the incidence and etiology of aneuploidy in male gametes, and propose an approach to systematically search for genetic components to human non- disjunction.